JPH08502971A - Farnesyl-protein transferase inhibitors - Google Patents

Abstract

  (57) [Summary] The present invention relates to compounds that inhibit farnesyl-protein transferase (FTase) and farnesylation of the oncogene protein Ras. The invention further relates to chemotherapeutic compositions containing the compounds of the invention, and methods for inhibiting farnesyl-protein transferase and farnesylation of the oncogene protein Ras.

Description

Detailed Description of the InventionInvention title   Farnesyl-protein transferase inhibitorsBackground of the Invention   RasThe gene is a number of human cancers including colorectal cancer, exocrine pancreatic cancer and myeloid leukemia Exists in the activated state in. By biological and biochemical studies of Ras action Ras is localized in the plasma membrane in order to transform cells and GT Since it should be bound to P, it has been shown to function similarly to the G regulatory protein. (Gibbs, J. et al.,Microbiol. Rev． 53: 171-2 86 (1989)). The morphology of Ras in cancer cells is the Ras protein in normal cells. Has a mutation that is distinguishable from quality.   At least three post-translational modifications are involved in Ras membrane localization, and these three modifications are not All are done at the C-terminus of Ras. Ras C-terminal is "CAAX" or "Cys-A" aa¹-Aaa²-Xaa "contains a sequence motif called the box (Aaa is Is an aliphatic amino acid and Xaa is any amino acid) (Willumsen ,Nature310: 583-586 (1984)). Other protein Ras-related GTP binding to those having the motif of Proteins (eg Rho, fungal mating factors etc.), nuclear lamins and transducy Γ subunit of   Ras is a Cys site by the isoprenoid farnesyl pyrophosphate (FPP) soin  vivoFarnesylated to form a thioether bond (Hanc ock et al.Cell  57: 1167 (1989); Casey et al.,Proc. Natl. Acad. Sci. USA   86: 8323 (1989)). Furthermore, Ha-Ras and N-Ras are located near the C-terminal Cys farnesyl acceptor. It is palmitoylated by forming a thioester on the Cys residue (Gu tierrez et al.,EMBO J.M.8: 1093-1098 (1989); Ha. ncock et al.,Cell  57: 1167-1177 (1989)). Ki-R as deletes the palmitate acceptor Cys. The last 3 RasC ends Amino acids in the protein are removed by proteolysis, and the new C-terminal is methyl esterified. (Hancock et al., Supra). Similar modifications to fungal mating factors and mammalian nuclear layers Take steps (Anderegg et al.,J. Biol. Chem.263: 1 8236 (1988); Farnsworth et al.,J. Biol. Chem ． 264: 20422 (1989)).   Ras farnesylation involves lovastatin (applicant) and compactin (Ha ncock et al., supra; Casey et al., supra; Schafer et al., supra.Science 245: 379 (1989)).in  vivoProved to be hindered It These agents are polyisoprenoid and farnesyl pyrophosphate precursors. It inhibits HMG-CoA reductase, which is the rate-limiting enzyme for the production of L. Precursor Farnesyl-protein trans using farnesyl pyrophosphate as quality Ferrase has been shown to be responsible for Ras farnesylation (Reis s et al.Cell62: 81-88 (1990): Schaber et al.,J. Bi ol. Chem ． , 265: 14701-14704 (1990); Schaf. er,Science, 249: 1133-1139 (1990); Mann. e,Proc. Natl. Acad. Sci USA, 87: 7541-7 545 (1990)).   Inhibition of farnesyl-protein transferase, And inhibition of farnesylation of Ras protein by Ras in normal cells To convert into cancer cells. Compounds of the Invention Inhibit Ras Farnesylation And soluble Ra that may act as a major negative inhibitor of Ras function as described below. produces s. Soluble Ras in cancer cells can be a major negative inhibitor, but normal Soluble Ras in cells does not become an inhibitor.  Ras cytosolic localization (Cys-Aaa¹-Aaa²-Xaa Box Membrane Dome Absent) and activated (remaining bound to GTP and impaired GTPase activity) forms Acts as a major negative Ras inhibitor of membrane-bound Ras function (Gibbs et al.,P roc. Natl. Acad. Sci. USA 86: 6630-6634 (19 89)). The cytosolic localized form of Ras with normal GTPase activity is an inhibitor Does not work as Gibbs et al.XenopusOocyte and lactate This effect was reported in mammalian cells.   Administration of compounds of the present invention to block Ras farnesylation results in Not only is the amount of Ras reduced, but Ras cytosole pools are generated. Live Sexualized Ras In tumor cells with, cytosolic pools are another antagon of membrane-bound Ras function. Acts as a nyst. In normal cells with normal Ras, Ras cytosaw Lupur does not act as an antagonist. Do not completely prevent farnesylation As long as the other farnesylated protein is able to maintain its function.   By adjusting the compound dose, farnesyl-protein transfer It can reduce or completely inhibit laccase activity. Adjust compound dose Reduces farnesyl-protein transferase enzyme activity by node Is undesirable due to interference with other metabolic processes that use the enzyme Useful to avoid side effects.   These compounds and their homologues are farnesyl-protein transferors. It is an inhibitor of ze. Farnesyl-protein transferase Lupyrophosphate was used to capture the Cys thiol group of the Ras CAAX box. It is covalently modified with a renesil group. Inhibiting HMG-CoA reductase Inhibition of farnesyl pyrophosphate biosynthesis further localized Ras membrane localization in vivo at o Can block and inhibit Ras function. Farnesyl-Protein Tolan Inhibition of spherase is more specific than that of common inhibitors of isoprene biosynthesis And has few side effects.   Tetrapeptide containing cysteine as amino terminal residue having CAAX sequence Has been demonstrated to inhibit Ras farnesylation (Schabe r et al., supra; Reiss et al., supra,PNAS, 88: 732-736 (1991). )). Such inhibitors are alternatives to the Ras farnesyl-transferase enzyme. Can function as a substrate for inhibition or can be a purely competitive inhibitor ( (U.S. Pat. No. 5,141,851, University of Texas).   The compounds of the present invention have the general structure C- [ΨCH containing two reducing peptide bonds.₂N H] Xaa¹-[ΨCH₂NR] Xaa²-Xaa³(In the formula, C is cysteine and , Xaa^1-3Is any amino acid and Xaa¹And Xaa²The nitrogen between is alkylated Has been described). The compound of the present invention is Ras farnesylt. It is a stable inhibitor of lancerase. As a result of the presence of the reducing amide bond, this Give these inhibitors metabolic stability and prevent ras farnesylationin vivo Can be inhibited. In addition, the first and second peptide bonds are reduced As a result, the intrinsic enzyme inhibitory activity can be unexpectedly increased. Xaa¹When Xaa²Chemical stability to these homologues due to the alkylation of the reactive nitrogen between And thus thatin vivoCan increase activity (cell culture) . The lactone or ester form of these inhibitors is the site of Ras farnesylation. Is a prodrug that effectively delivers active hydroxy acids or acids, respectively, to the intracellular compartments The view that it is particularly useful.   Therefore, the object of the present invention is to¹And Xaa²The nitrogen between is alkylated 2 A compound based on a tetrapeptide having one reduced amide bond, comprising: Inhibits arnesyl-protein transferase and induces oncogene protein R To develop a compound that inhibits asnes farnesylation. Of the present invention Another object is to provide a chemotherapeutic composition containing a compound of the invention and a compound of the invention. It is to develop a manufacturing method.Summary of the Invention   The present invention has two reducing amide linkages and provides farnesyl-protein Inhibits lancerase and causes tumor Tetrapeptide homologue that inhibits farnesylation of gene protein Ras Includes chemotherapeutic compositions containing a compound of the invention as well as methods of making the compounds of the invention. To do.   The compounds of the present invention have the formula: Represented byDetailed Description of the Invention   The compounds of the present invention inhibit farnesyl-protein transferase and tumors. It is useful for inhibiting farnesylation of the tumor gene protein Ras. First of the present invention According to an embodiment of the invention, the inhibitor of farnesyl-protein transferase is of formula I : (In the formula, R¹Is hydrogen, an alkyl group, an aralkyl group, an acyl group, an aracyl group, an aroyl group, An alkylsulfonyl group, an aralkylsulfonyl group or an arylsulfonyl group The alkyl group and the acyl group include a straight or branched chain hydrocarbon having 1 to 6 carbon atoms. See; R², R³And R^FourIs methionine sulfoxide or methionine Side chains of naturally occurring amino acids, including its oxidized form, which can be , Or a substituted or unsubstituted aliphatic, aromatic or heteroaromatic group such as allyl, Cyclohexyl, phenyl, pyridyl, imidazolyl or C2-C8 It may be a branched or unbranched saturated chain and the aliphatic substituent is an aromatic or heteroaromatic ring. May be substituted; R^FiveIs an alkyl group containing a straight or branched chain hydrocarbon having 1 to 6 carbon atoms, (It may be substituted with an aromatic ring or an aromatic heterocycle) And a pharmaceutically acceptable salt thereof.   According to a second aspect of the invention, a prodrug of the compound of formula I has the formula II: (In the formula, R¹Is hydrogen, alkyl group, aralkyl group, acyl group, ara Syl group, aroyl group, alkylsulfonyl group, aralkylsulfonyl group or ari Is a sulfonyl group, and the alkyl group and the acyl group are a straight chain or an alkyl group having 1 to 6 carbon atoms. Includes branched chain hydrocarbons; R², R³And R^FourMay be methionine sulfoxide or methionine sulfone A side chain of a naturally occurring amino acid, including its oxidized form, or substituted or non-substituted Substituted aliphatic, aromatic or heteroaromatic groups such as allyl, cyclohexyl, phenyl Nyl, pyridyl, imidazolyl or branched or unbranched saturated with 2 to 8 carbon atoms May be a chain, and the aliphatic substituent may be substituted with an aromatic ring or an aromatic heterocycle. ; R^FiveIs an alkyl group containing a straight or branched chain hydrocarbon having 1 to 6 carbon atoms, May be substituted with an aromatic ring or an aromatic heterocycle; R⁶Is a substituted or unsubstituted aliphatic, aromatic or heteroaromatic group, eg having 1 carbon atom ~ 8 branched or unbranched saturated chain, the aliphatic substituent is an aromatic ring or an aromatic heterocycle May be replaced with) And the pharmaceutically acceptable salts and disulfides thereof.   According to a third aspect of the invention, farnesyl-protein transferase Inhibitors of formula III: (In the formula, R¹Is hydrogen, an alkyl group, an aralkyl group, an acyl group, an aracyl group, an aroyl group, An alkylsulfonyl group, an aralkylsulfonyl group or an arylsulfonyl group The alkyl group and the acyl group include a straight or branched chain hydrocarbon having 1 to 6 carbon atoms. See; R²And R³Is methionine sulfoxide or its acid which may be methionine sulfone Side chains of naturally occurring amino acids, including modified forms, or substituted or unsubstituted fats Aliphatic, aromatic or heteroaromatic groups such as allyl, cyclohexyl, phenyl, Pyridyl, imidazolyl or branched or unbranched saturated chains having 2 to 8 carbon atoms Well, aliphatic substituents are aromatic Optionally substituted with a ring or aromatic heterocycle; R^FiveIs an alkyl group containing a straight or branched chain hydrocarbon having 1 to 6 carbon atoms, Optionally substituted with an aromatic ring or an aromatic heterocycle; n is 0, 1 or 2) And a pharmaceutically acceptable salt thereof.   According to a fourth aspect of the invention, a prodrug of the compound of formula III has the formula IV: (In the formula, R¹Is hydrogen, an alkyl group, an aralkyl group, an acyl group, an aracyl group, an aroyl group, An alkylsulfonyl group, an aralkylsulfonyl group or an arylsulfonyl group The alkyl group and the acyl group include a straight or branched chain hydrocarbon having 1 to 6 carbon atoms. See; R²And R³Is methionine sulfoxide or its acid which may be methionine sulfone Modified amino acids, including modified forms, or substituted or unsubstituted lipids. Aliphatic, aromatic or heteroaromatic groups such as allyl, cyclohexyl, phenyl, Pyridyl, imidazolyl or branched or unbranched saturated chains having 2 to 8 carbon atoms Well, the aliphatic substituent may be substituted with an aromatic ring or an aromatic heterocycle; R^FiveIs an alkyl group containing a straight or branched chain hydrocarbon having 1 to 6 carbon atoms, (It may be substituted with an aromatic ring or an aromatic heterocycle) Of compounds of formula (I) and pharmaceutically acceptable salts and disulfides thereof.   Preferred compounds of the present invention are N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -Methylpentyl] -N-methylisoleucylhomoserine, N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -Methylpentyl] -N-methylisoleucylhomoserine lactone, N- [2 (S)-(2 (R) -amino-3-mercaptope Ropyramino) -3 (S) -methylpentyl] -N-methylphenylalanylpho Moselin, N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -Methylpentyl] -N-methylphenylalanyl homoserine lactone, N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3- Methylbutyl] -N-methylphenylalanyl homoserine, N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3- Methylbutyl] -N-methylphenylalanyl homoserine lactone, 3 (S)-{N- [2 (S)-(2 (R) -amino-3-mercaptopropyla Mino) -3 (S) -methylpentyl] -N-methylisoleucylamino} -3- Methyltetrahydropyran-2-one, 2 (S)-{N- [2 (S)-(2 (R) -amino-3-mercaptopropyl acetate Mino) -3 (S) -methylpentyl] -N-methylisoleucylamino} -2- Methyl-5-hydroxypentanoic acid, 2 (S)-{N- [2 (S)-(2 (R) -amino-3- Mercaptopropylamino) -3 (S) -methylpentyl] -N-methylisolo Isylamino} -5-methyl-5-hydroxyhexanoic acid, N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -Methylpentyl] -N-methylnorvalylhomoserine, N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -Methylpentyl] -N-methylnorvalylhomoserine lactone, N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -Methylpentyl] -N-methylisoleucylmethionine, N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -Methylpentyl] -N-methylisoleucylmethionine methyl ester, N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -Methylpentyl] -N-methylphenylalanylmethionine, N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -Methylpentyl] -N-methyl Luphenylalanylmethionine methyl ester, 3 (S)-{N- [2 (S)-(2 (R) -amino-3-mercaptopropyla Mino) -3 (S) -methylpentyl] -N-methylisoleucylamino} -6, 6-dimethyltetrahydropyran-2-one, N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -Methylpentyl] -N-methylnorvalylmethionine, N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -Methylpentyl] -N-methylnorvalylmethionine methyl ester, N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -Methylpentyl] -N-methyl D-norvalylhomoserine, or N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -Methylpentyl] -N-methyl-D-norvalylhomoserine lactone, And pharmaceutically acceptable salts thereof.   The optimal compounds of the present invention are the following inhibitors and the corresponding lactone / ester prod Rag vs: N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -Methylpentyl] -N-methylisoleucyl homoserine N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -Methylpentyl] -N-methylisoleucyl homoserine lactone N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -Methylpentyl] -N-methylisoleucylmethionine N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -Methylpentyl] -N-methylisoleucylmethionine methyl ester And pharmaceutically acceptable salts thereof.   Amino acids disclosed in the present invention are represented by the following common three-letter and one-letter notations. It Alanine Ala A Arginine Arg R Asparagine Asn N Aspartic acid Asp D Asparagine or aspartic acid Asx B Cysteine Cys C Glutamine Gln Q Glutamic acid Glu E Glutamine or glutamic acid Glx Z Glycine Gly G Histidine His H Isoleucine Ile I Leucine Leu L Lysine Lys K Methionine Met M Phenylalanine Phe F Proline Pro P Serine Ser S Threonine Thr T Tryptophan Trp W Tyrosine Tyr Y Valine Val V   Pharmaceutically acceptable salts of the compounds of this invention are derived, for example, from non-toxic inorganic or organic acids. Includes conventional non-toxic salts of the compounds of the invention as formed. For example, such a convention Non-toxic salts for use are hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid. Salts derived from inorganic acids such as acetic acid, propionic acid, succinic acid, glyco Acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, Pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, ammonium Benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, Ruenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethione Acids, salts prepared from organic acids such as trifluoroacetic acid and the like can be mentioned.   The pharmaceutically acceptable salts of the compounds of this invention are prepared using conventional chemical compounds. It can be synthesized from the compound of the present invention containing a basic moiety by a conventional method. In general , The salt is a stoichiometric amount of the free base in a suitable solvent or various combinations of solvents. It is prepared by reacting with an excess of the desired salt-forming inorganic or organic acid.   The compounds of the present invention can be incorporated into their component compounds by conventional peptide synthesis methods and additional methods described below. It can be synthesized from mino acids. Standard methods for peptide synthesis are described, for example, in the following reference: Schroeder et al., “The   Peptides ", Vol. I, Academic Press 1965. Bodanszky et al., "Peptide Synthesis", Inte. rScience Publishers, 1966; McOmie (ed.) “P Protective Groups in Organic Chemistry ", Plenum Press, 1973; Barany et al.," The pep. tides: Analysis, Synthesis, Biology ”,2, Chapter 1, Academic Press, 1980; Stewart et al., "So. lid Phase Peptide Synthesis ”, Second Edition, Pie rc Chemical al Company, 1984. The teachings in these references are informative It is considered as a part of this specification as a material.   The compounds of the present invention were prepared according to other standard procedures known in the literature or as illustrated in the experimental procedures section. In addition to (for example, ester hydrolysis, cleavage of protective group, etc.), the reaction A to reaction shown in the reaction scheme Manufactured by using C. The main bond formation reactions are as follows. Reaction A: Cleavage of the protecting group using standard solution or solid phase method to form amide bond. Reaction B: with aldehyde using sodium cyanoborohydride or other reducing agent A reduced peptide subunit is prepared by reductive alkylation of an amine. Reaction C: Alkyl or aralkyl halide of reduced peptide subunit Alkylated with sodium cyanoborohydride or other reducing agents. The reduced peptide subunit is reductively alkylated with an aldehyde.   These reactions can be used sequentially to provide compounds of the invention, which The fragment synthesized using these reactions was then subjected to the alkylation shown in the reaction scheme. You may couple | bond by reaction.                             Reaction scheme A Reaction A. Coupling residues to form amide bonds                             Reaction scheme B Reaction B. Production of reduced peptide subunits by reductive alkylation                             Reaction scheme C Reaction C. Alkylation / reductive alkylation of reduced peptide subunits   In the above diagram, R^AAnd R^BIs R as defined above², R³Or R^FourAnd X is A leaving group, eg Br^-, I^-Or MsO^-And R⁷Is in the reductive alkylation process Than R^FiveIs defined to be generated.   The compounds of the invention are farnesyl-protein transferase and oncogene Prevents farnesylation of the child protein Ras. These compounds are mammals, It is particularly useful as a human drug. These compounds are administered to patients for the treatment of cancer. Can be given. Treatable with compounds of the invention Non-limiting examples of cancer types include colorectal cancer, exocrine pancreatic cancer and myeloid leukemia. Is.   When the compound of the present invention is administered to mammals, preferably humans, it may be administered alone. Good, but preferably in accordance with standard pharmaceutical practice, optionally at known sources such as alum. Pharmaceuticals in combination with a pharmaceutically acceptable carrier or diluent with juvant Used in a composition. The compound may be administered orally, intravenously, intramuscularly, intraperitoneally, It may be administered by parenteral routes such as subcutaneous and topical administration.   For oral use of the chemotherapeutic compounds of the present invention, selected compounds may be used, for example in tablets. It may be administered as an agent or capsule, or as an aqueous solution or suspension. Yes. For oral tablets, commonly used carriers are lactose and corns. It is a starch, and a lubricant such as magnesium stearate is generally added. Capsule shape Useful Diluents for Oral Oral Administration are Lactose and Dried Corn Starch . If aqueous oral suspensions are required, combine the active ingredient with emulsifying and suspending agents. Let If desired, a predetermined sweetening agent and / or flavoring agent may be added. Intramuscular, For intraperitoneal, subcutaneous and intravenous administration, usually a sterile solution of the active ingredient is prepared. However, the pH of the solution should be adjusted and buffered appropriately. In the case of intravenous administration, The total concentration of solutes should be adjusted to render the agent isotonic.   The present invention further provides a therapeutically effective amount of a compound of the present invention as a pharmaceutically acceptable key. Pharmaceutical composition useful for the treatment of cancer, administered in the presence or absence of a carrier or diluent It also affects things. A suitable composition of the present invention is a compound of the present invention and a pH value of, for example, 7.4. And a pharmaceutically acceptable carrier (eg, saline). The solution may be introduced into the patient's intramuscular bloodstream by local condensate injection.   When administering a compound of the invention to a human, the daily dosage will generally be that of an individual patient. It will be determined by the prescribing physician depending on age, weight, response and severity of symptoms.   According to one application, an appropriate amount of compound is administered to a patient undergoing treatment for cancer. The dosage is About 0.1 mg / kg body weight / day to about 20 mg / kg body weight / day, preferably 0.5 m g / kg body weight / day to about 10 mg / kg / body weight / day.                               Example   This example is for understanding the invention in detail. Individual materials used, The species and conditions are for the purpose of illustrating the invention in detail and limit its scope. Not a thing.                             Example 1 N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -Methylpentyl] -N-methylisoleucyl homoserine lactone and N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 (S) -Methylpentyl] -N-methylisoleucyl homoserine Process A:   N- (t-butoxycarbonyl) isoleucine           aldehyde   Goel, Krolls, Stier and Kesten [Organic S yntheses,67, 69 (1988)] in N- (t-butoxycal This compound was synthesized by applying to bonyl) isoleucine. Compound Obtained as a colorless oil, which was used without further purification.Process B:   N-[(2S)-(t-butoxycarbonyla           Mino) -3 (S) -methylpentyl) isolloy           Synbenzyl ester   N- (t-butoxycarbonyl) isoleucine aldehyde (8.0 g, 0.0 37 mol) and isoleucine benzyl ester p-toluenesulfonate salt (1 Dissolve 9.0 g, 0.048 mol) in MeOH (50 ml) under nitrogen at ambient temperature. And, with stirring, 3A molecular sieve (15 g) and triacetoxyborohydrogenated sodium (20.4 g, 0.096 mol). After 2 hours, the mixture was filtered and concentrated. Shrink and the residue is EtOAc (100 ml) and saturated NaHCO 3.₃Aqueous solution (100m l) and. The base layer was washed with EtOAc (2 x 50 ml) and the organic layers combined. And wash with brine and dehydrate (Na₂SO_Four)did. Filter, concentrate to dryness, and dry. Matography (SiO₂, Hexane: EtOAc, 9: 1) followed by the title compound Obtained 6.4 g (41%) as a white solid.¹HNMR (CD₃OD) δ 7.30 -7.45 (m, 5H), 5.18 (ABq, 2H), 3.40-3.45 (m , 1H), 3.12 (d, 1H, J = 6Hz), 2.70 (dd, 1H, J = 4) , 12 Hz), 2.37 (Dd, 1H, J = 4, 12 Hz), 2.63 to 2.76 (m, 1H), 1.4 5 to 1.61 (m, 2H), 1.46 (s, 9H), 1.05 to 1.26 (m, 2H), 0.82-0.95 (m, 12H).Process C:   N-[(2S)-(t-butoxycarbonyla           Mino) -3 (S) -methylpentyl) -N-me           Cyl isoleucine benzyl ester   N-[(2S)-(t-butoxycarbonylamino) -3 (S) -methylpen Tyl) isoleucine benzyl ester (0.8 g) 1.9 mmol) with acetone Dissolve in (3 ml), K₂CO₃(0.52 g, 3.8 mmol) and iodometa (1.2 ml) 19 mmol) and stirred at ambient temperature for 18 hours. reaction Mix the mixture with 5% NH_FourTreat with aqueous OH (10 ml), stir for 0.5 h, then concentrate. Reduce with EtOAc (20 ml) and H₂Partitioned with O (20 ml). The aqueous layer is E Wash with tOAc (2 x 20 ml), combine organic layers and₂O, 10% citric acid Wash sequentially with acid and brine and dry (Na₂SO_Four)did. Filter and concentrate to dryness Obtained 0.814 g (98%) of the title compound as a yellow oil.¹HNMR (CDC l₃) Δ7.32 to 7.41 (m, 5H), 5.11 to 5.24 (m, 2H), 3.58 to 3.72 (m, 1H), 2.8 to 3.0 (m, 1H), 2.20 to 2.65 (m,^-5H), 1.88 ~ 2.0 (m, 1H), 1.68 to 1.80 (m, 1H), 1.56 to 1.67 ( m, 1H), 1.45 (s, 9H), 1.29 to 1.42 (m, 2H), 1.1 2 to 1.28 (m, 1H), 0.98 to 1.09 (m, 1H), 0.80 to 0. 95 (m, 12H).Process D:   N-[(2S)-(t-butoxycarbonyla           Mino) -3 (S) -methylpentyl) -N-me           Chill isoleucine   N-[(2S)-(t-butoxycarbonylamino) -3 (S) -methylpen Cyl) -N-methylisoleucine benzyl ester (0.814 g, 1.87 mi Limol) was dissolved in methanol (25 ml) and EtOAc (25 ml) and % Palladium on carbon (0.1g) and hydrogenated at hydrogen balloon pressure for 4 hours. It was Filter and concentrate to dryness to give 0.614 g (95%) of the title compound as a white solid. Obtained.¹HNMR (CDCl₃) Δ 5.1-5.2 (m, 1H), 3.7-3.8. (M, 1H), 3.27 to 3.35 (m, 1H), 2.8 to 2.92 (m, 12H), 2.55 (s, 3H), 1.80 to 1.93 (m, 1H), 1.55-1.8 (m, 2H), 1.48 (s, 9H) , 1.23 to 1.42 (m, 1H), 1.05 to 1.2 (m, 1H), 0.82 ~ 1.03 (m, 12H).Process E:   N- [2 (S)-(t-butoxycarbonyla           Mino-3 (S) -methylpentyl] -N-methyl           Luisoleucyl homoserine lactone   N-[(2S)-(t-butoxycarbonylamino) -3 (S) -methylpen Chill) -N-methylisoleucine (1.05 g) 3.05 mmol) at ambient temperature Dissolve in DMF (10 ml) with stirring at EDC (0.64 g, 3.35 ml). Limol), HOBT (0.45 g) 3.35 mmol) and homoserine hydrochloride Processed in tons. Et₃Adjusted pH to 6 with N (0.40 ml, 2.9 mmol) Stirring was continued for 18 hours. The reaction mixture was concentrated, then EtOAc (50 m l) and H₂Partitioned with O (50 ml). The aqueous layer is EtOAc (3 x 20 ml) Washed with water, combined organic layers and saturated NaHCO 3.₃Wash with aqueous solution, brine and dehydrate (Na₂SO_Four)did. Chromatography by filtration and concentration Graphography (SiO₂, Hexane: EtOAc 3: 1 → 2: 1 → EtOAc) After, 0.78 g (60%) of the title compound was obtained.¹HNMR (CD₃OD) δ4. 59 (t, 1H, J = 10Hz), 4.47 (td) 1H, J = 2, 10Hz) 4.28 to 4.39 (m, 2H), 3.56 to 3.64 (m, 1H), 2.7 4 (d, 1H, J = 10 Hz), 2.5 to 2.7 (m, 2H), 2.3 to 2.4 2 (m, 2H), 2.29 (s, 3H), 1.75 to 1.92 (m, 2H), 1 ． 4 to 1.6 (m, 2H), 1.46 (s, 9H), 1.07 to 1.20 (m, 2H), 0.88-0.95 (m, 12H).Process F:   N- [2 (S) -amino-3 (S) -methylpe           Nyl] -N-methylisoleucyl homoserine           Lactone   N- [2 (S)-(t-butoxycarbonylamido) in EtOAc (50 ml). No) -3 (S) -methylpentyl] -N-methylisoleucyl homoserine lacto Solution (0.21 g, 0.5 mmol) at −20 ° C. for 0.5 hours with stirring. HCl gas was bubbled through. Purge the solution with argon for 0.5 hours , Then concentrated to give the title compound 0.21 g (100%) was obtained as a white solid.¹HNMR (CD₃OD) δ4. 46 to 5.05 (m, 2H), 4.28 to 4.38 (m, 1H), 3.54 to 3 ． 70 (m, 2H), 3.2 to 3.4 (m, 2H), 2.75 to 2.97 (m, 3H), 2.45 to 2.59 (m, 2H), 2.1 to 2.2 (m, 1H), 1. 72 to 1.92 (m, 2H), 1.50 to 1.63 (m, 1H), 1.18 to 1 ． 4 (m, 2H), 0.98 to 1.12 (m, 12H).Process G:   N- (t-butoxycarbonyl) -S-triphe           Manufacture of Nylmethyl cysteine aldehyde   Goel, Krolls, Stier and Kesten [Organic S yntheses,67, 69 (1988)] in N- (t-butoxycal This compound was synthesized by applying to bonyl) -S-trityl cysteine. did. The compound was obtained as a white solid and used without further purification.¹HNMR (CDCl₃) Δ 9.2 (1H, s), 7.5-7.1 (15H, m), 5.1 (1H, brd), 3.92 (1H, m), 2.85-2.5 (2H, m), 1 ． 4 (9H, s).Process H:   N- [2 (S)-(2 (R)-(t-butoxy           Carbonylamino) -3-triphenylmethyl           Mercaptopropylamino) -3 (S) -meth           Rupentyl] -N-methylisoleucyl homose           Phosphorus lactone   N- [2 (S) -amino-3 (S) -methylpentyl] -N-methylisolloy Sylhomoserine lactone (0.21 g, .0.6 mmol) was added to methanol (3 m 1) dissolved in KOAc (0.1 g, 1.0 mmol), 3A molecular sieve (0.5 g) ) And N- (t-butoxycarbonylamino) -S-triphenylmethyl system After treatment with inaldehyde (0.25 g, 0.6 mmol), cyanoborohydride Treat with sodium hydride (1M in THF) (1 ml) and stir at ambient temperature for 18 hours. did. The reaction mixture was filtered, EtOAc (20 ml) and saturated NaHCO 3.₃Aqueous solution Distributed to and. The organic layer was washed with brine and dried (Na₂SO_Four)did. Filtered, Concentration to dryness gives a solid product which is chromatographed (SiO 2₂, CH₂Cl₂ : MeOH 99: 1 → 97: 3) to give 0.12 g (33%) of the title compound. Obtained.¹HNMR (CD₃OD) δ7.21 to 7.42 (m, 15H), 4.42 ~ 4.56 (m, 2H), 4.25-4.34 (M, 1H), 3.62 to 3.72 (m, 1H), 2.63 to 2.80 (m, 3 H), 2.30 to 2.60 (m, 6H), 2.18 to 2.28 (m, 4H), 1 ． 81 to 1.93 (m, 1H), 1.54 to 1.78 (m, 2H), 1.45 ( s, 9H), 1.06 to 1.37 (m, 3H), 0.80 to 0.98 (m, 12 H).Process I:   N- [2 (S)-(2 (R) -amino-3-me           Lucaptopropylamino) -3 (S) -methyl           Pentyl] -N-methylisoleucyl homoseri           ContractThe   N- [2 (S)-(2 (R)-(t-butoxycarbonylamino) -3-tri Phenylmethylmercaptopropylamino) -3 (S) -methylpentyl] -N -Methyl isoleucyl homoserine lactone (0.12 g) 0.16 mmol) CH₂Cl₂Dissolve in (5 ml), CF₃CO₂H (TFA) (2.5 ml) and Treated with triethylsilane (0.10 ml, 0.64 mmol) at 0 ° C. at ambient temperature. ． Stir for 5 hours. The solution is concentrated to dryness and H₂Triturated with 0.1% TFA in O. Solid triphenylmethane was removed by filtration and the filtrate was lyophilized to give the title compound. 0.07g (5 9%) was obtained.¹HNMR (CD₃OD) δ 4.45-4.55 (m, 2H), 4 ． 28-4.35 (m, 1H), 3.52-3.61 (m, 1H), 3.49 ( d, 1H, J = 6 Hz), 3.18 to 3.25 (m, 1H), 3.02 to 3.1. 6 (m, 4H), 2.92 (t, 1H, J = 6Hz), 2.85 (t, 1H, J) = 6 Hz), 2.78 (s, 3H), 2.42 to 2.56 (m, 2H), 2.0 5 to 2.15 (m, 1H), 1.83 to 1.94 (m1IH), 1.58 to 1. 61 (m, 1H), 1.40 to 1.52 (m, 1H), 1.22 to 1.4 (m, 2H), 0.93 to 1.06 (m, 12H). C₂₀H₄₀N_FourO₃S / 3CF₃CO₂ H ・ 0.6H₂Calculated for O: C, 40.72; H, 5.77; N, 7.3. 1. Found: C, 40.72; H, 5.99; N5 7.69.Process J:   N- [2 (S)-(2 (R) -amino-3-me           Lucaptopropylamino) -3 (S) -methyl           Pentyl] -N-methylisoleucyl homoseri           The   N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 (S) -Methylpentyl] -N-me Tyl isoleucyl homoserine lactone (0.0025g, 0.00326 millimo Solution) in MeOH (0.0506 ml) and 1N NaOH (0.0134 ml). ml) was added followed by MeOH (0.262 ml). Lactone hide Conversion to roxic acid is by HPLC analysis and / or¹Confirmed by 1 H NMR analysis.                             Example 2 N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -Methylpentyl] -N-methylphenylalanyl homoserine lactone and N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -Methylpentyl] -N-methylphenylalanyl homoserine   The title compound was used according to the method of Example 1 Ruester was produced by substituting phenylalanine methyl ester. Process D Instead, the methyl ester was hydrolyzed as outlined below.Process D:   N-[(2S)-(t-butoxycarbonyla           Mino) -3 (S) -methylpentyl) -N-me           Tylphenylalanine   N-[(2S)-(t-butoxycarbonylamino) -3 (S) -methylpen Chill) -N-methylphenylalanine methyl ester (1.92 g, 0.004 9 mol) was dissolved in MeOH (20 ml) and 4 equivalents of 1N NaOH (19.56). ml, 0.0196 mol) and stirred at ambient temperature for 18 hours. Reaction mixture Was concentrated to remove methanol, then 1N HCl (19.56 ml) 0.0 It was neutralized with 196 mol) and extracted with EtOAc (3 x 30 ml). Combine the organic layers And wash with brine and dehydrate (Na₂SO_Four)did. Filter and concentrate to dryness for title 1.6 g (86%) of the compound was obtained, which was used without further purification.   Use Steps E-I of Example 1 to obtain the title compound as the trifluoroacetate salt. Also, melting point 74-80 ° C.¹HNMR (CD₃OD) δ 7.2-7.4 (m, 5H) 4.41 to 4.48 (m, 1H), 4.24 (q, 1H, J = 9Hz), 4. 15 (t, 1H, 11 Hz), 3.97 (dd, 1H, J = 6, 11 Hz), 3 ． 53 (t, 1H, J = 6Hz), 2.95 to 3.4 (m, 8H), 2.82 to 2.92 (m, 1H), 2.81 (s, 3H), 2.12 to 2.3 (m, 2H) 1.82 to 1.95 (m, 1H), 1. 35 to 1.52 (m, 1H), 1.15 to 1.23 (m, 1H), 0.85 to 1 ． 03 (m, 6H). C_{twenty three}H₃₈N_FourO₃S ・ 2.85CF₃CO₂Calculation for H Values: C, 44.44; H, 5.31; N, 7.22. Found: C, 44.36; H, 5.46; N, 7.50.   The lactone was converted to the hydroxy acid by the method described in Step J of Example 1.                             Example 3 N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3- Methylbutyl] -N-methylphenylalanyl homoserine lactone and N- [2 (S)-(2 (R) -Amino-3-mercaptopropylamino) -3-methylbutane Cyl] -N-methylphenylalanyl homoserine   The title compound was the isoleucine used in Step A according to the methods of Examples 1 and 2. The derivative was produced by substituting Nt-butoxycarbonylvaline. Homoserine la The kutone was obtained as the trifluoroacetate salt. Melting point 55-60 [deg.] C.¹HNMR (CD₃ OD) δ7.21 to 7.39 (m, 5H), 4.43 (td, 1H, J = 4, 1) 0 Hz), 4.22 (q, 1H, J = 9 Hz), 4.12 (t, 1H, J = 10 Hz), 3.50 to 3.5 8 (m, 1H), 3.02 to 3.35 (m, 8H), 2.82 to 2.90 (m, 2H), 2.82 (s, 3H), 2.04 to 2.28m, 3H), 1.05 (d 3H, J = 6Hz), 0.98 (d, 3H, J = 6Hz). C_{twenty two}H₃₆N_FourO₃S ・ 3CF₃CO₂H-H₂Calculated for O: C, 42.21; H, 5.19; N , 7.03. Found: C, 42.17; H, 5.03; N5 7.26.   The hydroxy acid was prepared in situ by Step J of Example 1.                             Example 4 N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -Methylpentyl] -N-methylnorvalylhomoserine lactone and N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 (S) -Methylpentyl] -N-methylnorvalylhomoserine   The title compound is the isoleucine used in Step B according to the methods of Examples 1 and 2. Benzyl ester is norvaline It was prepared by substituting the chill ester. Homoserine lactone with trifluoroacetate I got it. Melting point 50-55 [deg.] C.¹HNMR (CD₃OD) δ 4.45-4.51 ( m, 2H^-), 4.25 to 4.38 (m, 1H), 3.75 to 3.82 (m, 1) H), 3.43 (t, 1H, J = 6Hz), 2.82-3.15m, 7H), 2 ． 88 (s, 3H), 2.4 to 2.55 (m, 2H), 1.78 to 1.97 (m 3H), 1.32 to 1.48 (m, 3H), 1.15 to 1.32 (m, 1H) , 1.01 (q, 6H, J = 9 Hz), 1.90 (d, 3H, J = 7 Hz). C₁₉ H₃₈N_FourO₃S / 3CF₃CO₂H 0.75H₂Calculated for O: C, 39. 60; H, 5.65; N, 7.39. Found: C, 49.58; H, 5.65; N, 7.48.   The hydroxy acid was prepared in situ by Step J of Example 1.                             Example 5 N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -Methylpentyl] -N-methylisoleucylmethionine methyl ester   The title compound was prepared by the method of steps AI of Example 1. The homoserine lactone of Step E was prepared by substituting methionine methyl ester. Freezing After drying, trifluoroacetic acid salt was obtained.¹HNMR (CD₃OD) δ 4.65-4 ． 73 (m, 1H), 3.75 (s, 3H), 3.42 to 3.54 (m, 2H) 2.87 to 3.22 (m, 7H), 2.73 (s, 3H), 2.49 to 2.5 8 (m, 2H), 2.12 to 2.25 (m, 1H), 2.10 (s, 3H), 1 ． 98-2.1 (m) 2H), 1.8-1.92 (m, 1H), 1.62-1. 77 (m, 1H), 1.21 to 1.48 (m, 3H), 0.9 to 1.05 (m, 12H). C_{twenty two}H₄₆N_FourO₃S₂・ 2.25CF₃CO₂Calculated value for H: C, 4 3.28; H, 6.61; N, 7.62. Found: C, 43.23; H, 6.5. 4; N, 7.81.                             Example 6 N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -Methylpentyl] -N-methylisoleucylmethionine Process A:   N- [2 (S)-(2 (R)-(t-butoxy           Carbonylamino-3-triphenylmethyl ester           Lucaptopropylamino) -3 (S) -methyl           Pentyl] -N-methylisoleucylmethionine           The   N- [2 (S)-(2 (R)-(t-butoxycarbonylamino-3-trif Phenylmethylmercaptopropylamino) -3 (S) -methylpentyl] -N- Methyl isoleucyl methionine methyl ester (0.19 g) 0.232 mm (Prepared as intermediate in Example 5) in MeOH (4 ml), At room temperature by treatment with NaOH solution (0.927 ml, 0.927 mmol). Stir for 3.5 hours. The reaction mixture is concentrated and the residue is diluted with H₂Dissolve in O (20 ml) And neutralized with 1N HCl (0.927 ml, 0.927 mmol), EtOA Extracted with c (3 x 20 ml). Combine the organic layers, wash with brine, and dry (N a₂SO_Four)did. Filter and concentrate to dryness to give 0.18 g (96%) of the title compound, It was used without further purification.Process B:   N- [2 (S)-(2 (R) -amino-3-me           Lucaptopropylamino) -3 (S) -methylpentyl]           -N-methyl isoleucyl methionine   N- [2 (S)-(2 (R)-(t-butoxycarbonyl) Ruamino-3-triphenylmethylmercaptopropylamino) -3 (S) -me Cylpentyl] -N-methylisoleucylmethionine^-(0.18g) 0.22 3 mmol) in CH₂Cl₂Dissolve in (4 ml), CF₃CO₂H (2 ml) and g Treated with triethylsilane (0.143 ml, 0.893 mmol) at ambient temperature Stir for 1.5 hours. The reaction mixture was concentrated, hexane (20 ml) and H 2₂In O Partition with 0.1% TFA (20 ml) and freeze dry the aqueous layer to give the crude product. , It was purified by preparative HPLC and lyophilized again to give the title compound 0.075 g (43%) was obtained as the trifluoroacetate salt.¹HNMR (CD₃OD) δ4. 59 to 4.68 (m, 1H), 3.47 to 3.6 (m, 2H), 3.16 (d, 1H, J = 6Hz), 3.06 (s, 3H), 2.85 to 3.03 (m, 3H) 2.77 (s) 3H), 2.5 to 2.7 (m, 2H), 2.17 to 2.29 ( m, 1H), 2.11 (s, 3H), 1.98 to 2.1 (m, 2H), 1.8 to 1.93 (m, 1H), 1.58 to 1.75 (m, 1H), 1.2 to 1.5 (m 3H), 0.85 to 1.05 (m, 12H). C_{twenty one}H₄₄N_FourO₃S₂・ 2.75 CF₃CO₂Calculated for H: C, 40.89; H, 6.05; N, 7.20. Found: C, 41.18; H, 6.21; N, 7 ． 25.                             Example 7 N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -Methylpentyl] -N-methylphenylalanylmethionine methyl ester Le   The title compound is prepared according to the method of Example 5 from step B of isoleucine benzyl ester. Produced by substituting phenylalanine methyl ester with trifluoroacetate Isolated.¹HNMR (CD₃OD) δ 7.26 to 7.37 (m, 5H), 4 ． 49-4.55 (m, 1H), 4.16 (t, 1H) J = 8Hz), 3.70 (S, 3H), 3.53 (t, 1H, J = 6Hz), 2.9 to 3.3 (m, 7H) ), 2.89 (d, 2H) J = 6 Hz), 2.70 (s, 3H), 2.24-2 ． 6 (m, 2H), 2.05 (s, 3H), 1.8 to 2.17 (m, 3H), 1 ． 33-1.48 (m, 1H), 1.18-1.3 (m, 1H), 0.9-1. 0 (m, 6H). MS (M + 1) 513.                             Example 8 N- [2 (S)-(2 (R) -amino-3-mercaptope Ropyramino) -3 (S) -methylpentyl] -N-methylphenylalanylme Thionine   The title compound was prepared from the intermediate obtained in Example 7 by the method of Example 6. , As a trifluoroacetate salt.¹HNMR (CD₃OD) δ7.24-7 ． 4 (m, 5H), 4.4 to 4.5 (m, 1H), 4.12 (t, 1H, J = 8) Hz), 3.45 to 3.52 (m, 1H), 2.8 to 3.25 (m, 7H), 2 ． 66 (s, 3H), 2.6 to 2.7 (m, 1H), 2.23 to 2.5 (m, 2 H), 2.05 to 2.2 (m, 1H), 2.04 (s, 3H), 1.9 to 2.0. 4 (m, 2H), 1.76 to 1.9 (m, 1H), 1.12 to 1.46 (m, 2 H), 0.85-1.0 (m, 6H). C_{twenty four}H₄₂N_FourO₃S₂・ 3CF₃CO₂H 0.5CH₃Calculated for CN: C, 43.22; H, 5.44; N, 7.3. 2. Found: C, 43.22; H, 5.67; N5 7.68.                             Example 9 N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -Methylpentyl] -N-methylnorvalylmethionine methyl ester   The title compound was prepared according to the methods of Examples 1 and 2 from step B isoleucine benzyl. The ester was replaced with norvaline methyl ester and the homoserine lactone of step E was substituted. Was produced by substituting methionine methyl ester and step C by the following procedure .Process C:   N-[(2S)-(t-butoxycarbonyla           Mino) -3 (S) -methylpentyl) -N-me           Cylnorvaline methyl ester   N-[(2S)-(t-butoxycarbonylamino) -3 (S) -methylpen Chill) norvaline methyl ester (1.15 g, 3.6 mmol) in MeOH (15 ml), acetic acid (0.21 ml, 3.6 mmol), formaldehyde Hid (H₂37% in O) (0.61 ml, 7.2 mmol) and cyanoborohydrate Sodium arsenide (0.34 g, 5.4 mmol) was added to the algo with stirring. And ambient temperature. After 4 hours, the reaction mixture was concentrated and washed with EtOAc (20 ml) and saturated NH_FourPartition with an aqueous OH solution (20 ml) and dehydrate the organic layer (Na₂S O_Four) And concentrated to give 1.03 g (83%) of the title compound as a colorless oil.¹H NMR (CD₃OD) δ3.68 (s, 3H), 3.5 2 to 3.6 (m, 1H), 3.27 (t, 1H, J = 8Hz), 2.66 (dd 1H) J = 5,12 Hz), 2.42 (dd, 1H, J = 5,12 Hz),^- 2.28 (s, 3H), 1.57 to 1.69 (m, 3H), 1.44 (s, 9H ), 1.2 to 1.5 (m, 3H), 1.0 to 1.2 (m, 1H), 0.86 to 1 ． 0 (m, 9H).   The title compound was isolated as the hydrochloride salt according to Steps DI of Example 1.¹HNM R (CD₃OD) δ 4.66 to 4.72 (m, 1H), 3.89 to 3.95 (m 1H), 3.74 (s, 3H), 3.45 to 3.6 (m, 1H), 3.1 to 3 ． 4 (m, 4H), 2.94 (s, 3H), 2.89 to 3.2 (m, 3H), 2 ． 58 to 2.73 (m, 2H), 2.12 (s, 3H), 1.88 to 2.25 ( m, 4H), 1.2 to 1.65 (m, 5H), 0.91 to 1.1 (m, 9H). C_{twenty one}H₄₄N_FourO₃S₂Calculated for 4.5 HCl: C, 40.11; H, 7. 77; N, 8.91. Found: C, 40.03; H, 7.86: N, 8.65.                             Example 10 N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -Methylpentyl] -N-methyl Renorvalyl methionine   The title compound was hydrolyzed and deprotected from the precursor of Example 9 by the method of Example 6. Prepared after protection and isolated as the trifluoroacetate salt.¹HNMR (CD₃OD ) Δ4.57 to 4.66 (m, 1H), 3.80 (t, 1H, J = 8Hz), 3 ． 04-3.5 (m, 7H), 2.8-2.97 (m, 4H), 2.90 (s, 3H), 2.47 to 2.7 (m, 2H), 2.13 to 2.3 (m, 1H), 2. 09 (s, 3H), 1.8-2.0 (m, 2H), 1.34-1.6 (m, 2H ), 1.2-1.32 (m, 1H), 0.88-1.1 (m, 9H). C₂₀H₄₂ N_FourO₃S₂・ 3CF₃CO₂H ・ H₂Calculated for O: C, 38.51; H, 5. 84; N, 6.91. Found: C, 38.51; H, 5.71; N5 7.23.                             Example 11 N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -methylpentyl] -N-methyl-D-norvalylhomoserine lactone and And N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 (S) -Methylpentyl] -N-methyl-D- Norvalil homoserine   The title compound was prepared according to the method of Example 1 to give isoleucylbenzyl ester D- Produced by substituting norvaline methyl ester and isolated as trifluoroacetate did.¹HNMR (CD₃OD) δ 4.49 (t, 1H, J = 9Hz), 4.28 -4.3 (m, 1H), 3.74-3.8 (m, 1H), 3.45-3.5 (m 1H), 2.8 to 3.15 (m, 8H), 2.86 (s, 3H), 2.55 2.63 (m, 1H), 2.26 to 2.73 (m, 1H), 1.75 to 1.95 (M, 3H), 1.18 to 1.54 (m, 5H), 0.88 to 1.02 (m, 9) H). C₁₉H₃₈N_FourO₃S / 3CF₃CO₂H 0.75H₂Calculated value for O: C , 39.60; H, 5.65; N, 7.39. Found: C, 39.62; H, 6 ． 03; N, 7.23.   The hydroxy acid was prepared in situ by Step J of Example 1.                             Example 12 3 (S)-{N- [2 (S)-(2 (R) -amino-3-mercaptopropyla Mino) -3 (S) -methylpentyl] -N-methylisoleucylamino} -6, 6-dimethyl ether Trahydropyran-2-one and 2 (S)-{N- [2 (S)-(2 (R) -a Mino-3-mercaptopropylamino) -3 (S) -methylpentyl] -N-me Tyl isoleucylamino} -5-methyl-5-hydroxyhexanoic acid Process A:   2-N- (t-butoxycarbonyl) amino-           5-hydroxy-5-methylhexanoic acid   N- (t-butoxycarbonyl) glutamic acid-5- in THF (32 ml) To a solution of methyl ester (2.52 g, 0.0096 mol) was added a reaction temperature of -60. Methyllithium (in ether) under argon with stirring at a rate to keep it below ℃ 1.4 M) (30.2 ml, 0.042 mol) was added. After addition, mix Stir at −70 ° C. for 1 hour, then add to 10% citric acid solution (30 ml) and add E Extracted with tOAc (3 x 30 ml). Combine the EtOAc layers and wash with brine And dehydrated (Na₂SO_Four)did. After filtration and concentration, chromatography (SiO 2₂ , CHCl₃: MeOH: HOAc 90: 9: 1) by title 1.2 g (48%) of the compound was obtained as a yellow oil which solidified on standing.¹ HNMR (CDCl₃) Δ 5.28 (br s, 1H), 4.35 to 4.43 ( m, 1H), 1.75 to 2.0 (m, 2H), 1.58 (t, 2H, 9Hz), 1.46 (s , 9H), 1.24 (s, 6H).Process B:   3 (S)-(t-butoxycarbonyl) amino           -6,6-Dimethyltetrahydropyran-2-           on   2-N- (t-butoxycarbonyl) amino-5-hydroxy-5-methyl Xanthic acid (1.06 g) 4.05 mmol), dicyclohexylcarbodiimide (DCC) (1.01 g, 4.86 mmol) and 4-dimethylaminopyridine (DMAP) (0.05 g, 0.4 mmol) was stirred under argon at ambient temperature. While CH₂Cl₂It was dissolved in (40 ml). After 0.5 hours, the reaction mixture was filtered To remove dicyclohexylurea and the filtrate was concentrated to EtOAc (100 ml). Partitioned with 10% citric acid solution (50 ml). The organic layer is separated and H₂O (3 x 50m1), washed with brine (1 x 50ml) and dried (Na₂SO_Four)did. Ro Filtration, concentration and chromatography (SiO₂, EtOAc: hexane 1: 2) Gave 0.6 g (61%) of the title compound as a white solid.¹HNMR (C DCl₃) Δ5.33 (br s, 1H), 4.04 to 4.17 (m, 1H), 2.37 to 2.48 (m, 1H), 1.8 to 2.0 (m, 3H), 1. 45 (s, 9H), 1.41 (s, 6H).Process C:   Hydrochloric acid 3 (S) -amino-6,6-dimethyltet           Lahydropyran-2-one   3 (S)-(t-butoxycarbonyl) amino-6,6-dimethyltetrahydr Ropran-2-one (0.36 g, 1.48 mmol) in EtOAc (30 ml ), Treated with HCl gas at −50 ° C. for 20 minutes, and stored at −30 to −50 ° C. for 20 minutes. Stir for minutes. Bubble argon through the solution for 10 minutes and then concentrate the solution to title. 0.265 g (100%) of the compound was obtained as a white solid.¹HNMR (CD₃OD) δ 4.05 to 4.15 (m, 1H), 2.2 to 2.32 (m, 1H), 2.0 to 2.15 (m, 3H), 1.48 (s, 3H), 1.43 (s, 3H).Process D:   3 (S)-{N- [2 (S)-(2 (R) -a           Mino-3-mercaptopropylamino) -3           (S) -Methylpentyl] -N-methylisolo           Isylamino} -6,6-dimethyltetrahydr           Lopyran-2-on   The title compound was prepared according to the method of Example 1 and the homoserine lactone in step E was converted to hydrochloric acid 3 Made by substituting (S) -amino-6,6-dimethyltetrahydropyran-2-one I made it. The title compound was obtained as the trifluoroacetate salt.¹HNMR (CD₃OD) δ 4.1 to 4.2 (m, 1H), 3.55 (d, 2H, J = 6 Hz), 3.0 to 3.3 (m, 6H), 2.90 (t, 2H, 6Hz), 2.81 (s, 3H), 2.28 to 2.39 (m, 1H), 1.82 to 2.15 (m, 5H), 1. 5 5 to 1.6 (m, 1H), 1.53 (s, 3H), 1.45 (s, 3H), 1. 2-1.4 (m, 2H), 0.92-1.04 (m, 12H). C_{twenty three}H₄₆N_FourO₃ S / 3CF₃CO₂H / 1.5H₂Calculated for O: C, 42.07; H, 6. 33; N, 6.77. Found: C, 42.20; H5 6.10; N5 7.16.   The hydroxy acid was prepared in situ by Step J of Example 1.                             Example 13 3 (S)-{N- [2 (S)-(2 (R) -amino-3-mercaptopropyla Mino) -3 (S) -methylpentyl] -N-methylisoleucylamino} -3- Methyl tetrahi Doropyran-2-one and 2 (S)-{N- [2 (S)-(2 (R) -amino- 3-Mercaptopropylamino) -3 (S) -methylpentyl] -N-methylyl Soleucylamino} -2-methyl-5-hydroxypentanoic acid Step A :2-amino-2-methyl-5-hydroxypen           Tanoic acid   Finely ground racemic α-methylglutamic acid (5.0 g, 0.029 mol) Was suspended in THF (30 ml) and triethylborane (1M in THF, 32. 32 ml, 0.032 mol) and heated at reflux for 36 hours. After cooling to 0 ℃ , Borane (1M) in THF (35.26 ml, 0.035 mol) was added dropwise to the solution. Then, the mixture was stirred at 0 ° C. for 3 hours. The mixture was quenched with 5% aqueous HCl (30 ml). Quench, stir for 0.5 h, concentrate on a rotary evaporator and concentrate the residue with 5% HCl (4 4 ml) and heated at reflux for 0.75 hours. After cooling and concentration, the residue is treated with M Dissolve in OH (50 ml), concentrate and repeat this procedure 3 times to give the title compound 5 ． 69 g were obtained, which was not purified.Process B :2- (t-butoxycarbonyl) amino-2-           Methyl-5-hydroxypentanoic acid   2-Amino-2-methyl-5-hydroxypentanoic acid (5.69 g, 0.03 1,2-dimethoxyethane (DME) (60 ml) while stirring 1 mol) at 0 ° C. ) And H₂It was dissolved in O (30 ml). The pH of the solution was 9- Adjust to 10, then DME (60 ml) and H₂Di-t- in O (30 ml) Butyl dicarbonate (7.45 g, 0.034 mol) was added dropwise, during which 1 N NaOH solution was added simultaneously to maintain the mixture at pH 9-10. Basic p The reaction mixture was allowed to stand at ambient temperature with occasional addition of 1 N NaOH to maintain H. Stir for 48 hours, then concentrate to ether and H.₂Partitioned with O. 10 aqueous layers Acidified with% citric acid solution and extracted with EtOAc (3 x 50 ml). Organic layer Combined, washed with brine and dried (Na₂SO_Four)did. Filter and concentrate to dryness 3.0 g of the crude title compound was obtained.Process C:   3- (t-butoxycarbonyl) amino-3-           Methyl tetrahydropyran-2-one   2- (t-butoxycarbonyl) amino-2-methyl-5-hydroxypenta Acid (3.0 g, 0.012 mol) and EDC (2.56 g, 0.013 mol) To DMF (2 0 ml) and stirred at ambient temperature for 18 hours. The reaction mixture was concentrated to dryness and the residue Distillate the mixture with EtOAc (30 ml) and H₂Partition with O (30 ml) and separate the organic layer Then wash with brine and dehydrate (Na₂SO_Four)did. Filtration, concentration and chromatograph Fee (SiO₂, EtOAc: hexane 1: 3) to give the title compound 0.8 6 g (31%) were obtained.¹HNMR (CDCl₃) Δ5.1 (br s, 1H), 4.35 to 4.55 (m, 2H), 2.49 to 2.64 (m, 1H), 1.78 -2.1 (m, 3H), 1.45 (s, 3H), 1.41 (s, 9H).Process D:   Hydrochloric acid 3-amino-3-methyltetrahydropyra           N-2-on   The title compound was prepared as described in Example 12, Step C, and the resulting product was further purified. Used without purification.Process E :3 (S)-{N- [2 (S)-(2 (R) -a           Mino-3-mercaptopropylamino) -3           (S) -Methylpentyl] -N-methylisolo           Isylamino} -3-methyltetrahydropyra           N-2-on   The title compound was prepared according to the method of Example 1 in the homolog of Step E. Serine lactone becomes 3-amino-3-methyltetrahydropyran-2-one hydrochloride It was replaced and manufactured. The title compound was obtained as the trifluoroacetate salt.¹HNMR ( CD₃OD) δ 4.42 to 4.55 (m, 2H), 3.48 to 3.6 (m, 2H) ), 3.17 to 3.28 (m, 1H), 2.88 to 3.15 (m, 5H), 2. 79 (s, 3H), 2.3 to 2.45 (m, 1H), 1.97 to 2.18 (m, 2H), 1.82 to 1.98 (m, 3H), 1.6 to 1.73 (m, 1H), 1 ． 56 (s, 3H), 1.21 to 1.5 (m, 4H), 0.86 to 1.05 (m , 12H). C_{twenty two}H₄₄N_FourO₃S / 3CF₃CO₂Calculated for H: C, 42.7 5; H, 6.02; N, 7.12. Found: C, 42.79; H, 6.18; N. 7.19.   The hydroxy acid was prepared in situ by Step J of Example 1.                             Example 14 In vitro inhibition of ras farnesyl transferase   Farnesyl-protein transferase (FTase) from bovine brain DEAE-Sephacel (Pharmacia, 0 → 0.8M NaCl) Gradient elution), N-octyl agarose (Sigma, 0 → 0.6 M Na Cl gradient elution) and Mono Q HPLC column (Pharmacia, 0 → 0.3 M NaCl gradient). 3.5μ MRas-CVLS, 0.25 μM [³H] FPP and specified compounds are partially purified Incubated with the cy enzyme preparation or the recombinant human enzyme preparation. Shown in Table 1 below FTase data can be found in Pompliano et al., Biochemistry.Three 1 , 3800 (1992), the test compound induces RAS farnesylation.in   vitroShows the ability to inhibit. * (IC50 is the concentration of the test compound that produces 50% inhibition of FTase under the stated assay conditions. Is)                             Example 15 in vivo ras farnesylation assay   The cell line used in this assay expresses the virus Ha-rasp21 vr It is an as system. The assay is performed by DeBlue, J. et al. E. FIG. Et al, Cancer Rese arch51, 712-717, (1991). 1 Cells grown in 0 cm dishes to a confluency of 50-75% were treated with test compound (with solvent The final concentration of some methanol or dimethylsulfoxide was 0.1%). 37 After 4 hours at ℃, 10% standard DMEM, 2% fetal bovine serum and And 400 μCi [³⁵S] Methionine (1000 Ci / mmol) -free Methion The cells were labeled with 3 ml of thionine DMEM. After an additional 20 hours, buffer the cells for lysis Solution (1% NP40 / 20 mM HEPES, pH 7.5 / 5 mM MgCl₂/ 1 mM DTT / 10 μg / ml aprotinin / 2 μg / ml leupeptin / 2μ g / ml antipine / 0.5 mM PMSF) and dissolve the lysate. Clarified by centrifugation at 100,000 xg for 45 minutes. Equal number of acid precipitation coun IP buffer (lysis buffer without DTT) in an aliquot of the lysate containing In addition, 1 ml was added to the ras-specific monoclonal antibody Y13-259 (Furt h, M. E. FIG. Et al., J. Virol.43, 294-304 (1982)) Allowed to settle. After incubation of the antibody for 2 hours at 4 ° C, protein A-rabbit 45 μl of 200 pl of 25% suspension of Sepharose coated with anti-rat IgG Added over minutes. The immunoprecipitate was washed with IP washing buffer (20 nM HEPES, pH 7.5 / 1 mM EDTA / 1% Triton X-100 / 0.5% de Oxycholate / 0.1% SDS / 0.1M NaCl), washed 4 times, SDS -PA Boiled in GE sample buffer and loaded on a 13% acrylamide gel. Before dye When the edge reaches the bottom, fix the gel, soak it in Enlightening and let it dry. , Subjected to autoradiography. Farnesylated ras protein and non-pha Comparing the intensities of the bands corresponding to the Renesylated ras protein, farnesyl The percentage inhibition of protein transfer was determined. Data for representative test compounds are shown in Table 2. You

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification code Internal reference number FI C07C 323/58 7419-4H C07K 5/06 8318-4H 5/062 ZNA 8318-4H 5/065 8318-4H 5 / 068 8318-4H 5/072 8318-4H 5/078 8318-4H (81) Designated country EP (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC , NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AU, BB, BG, BR, BY, CA. , CZ, FI, HU, JP, KR, KZ, LK, LV, MG, MN, MW, NO, NZ, PL, RO, RU, SD, SK, UA, US, UZ (72) Inventor Graham, Samuel A Le United States, Pennsylvania 19473, Swinksville, Wittland Drive 325

Claims (1)

[Claims] 1. Formula I: (In the formula, R ¹ is hydrogen, an alkyl group, an aralkyl group, an acyl group, an aracyl group, an aroyl group, an alkylsulfonyl group, an aralkylsulfonyl group or an arylsulfonyl group, and the alkyl group and the acyl group each have 1 to 6 carbon atoms. R ² , R ³ and R ⁴ are side chains of naturally occurring amino acids, including their oxidized forms which may be methionine sulfoxide or methionine sulfone, or substituted or unsubstituted It may be an aliphatic, aromatic or heteroaromatic group such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or a branched or unbranched saturated chain having 2 to 8 carbon atoms, and the aliphatic substituent is an aromatic ring or aromatic ring. It may be substituted with group heterocycle; R ⁵ is an alkyl group containing a straight or branched chain hydrocarbon having 1 to 6 carbon atoms, aromatic It is substituted on the ring or aromatic heterocyclic ring represented by may also), farnesyl - compounds and pharmaceutically acceptable salts thereof to inhibit protein transferase. 2. Formula II: (In the formula, R ¹ is hydrogen, an alkyl group, an aralkyl group, an acyl group, an aracyl group, an aroyl group, an alkylsulfonyl group, an aralkylsulfonyl group or an arylsulfonyl group, and the alkyl group and the acyl group each have 1 to 6 carbon atoms. R ² , R ³ and R ⁴ are side chains of naturally occurring amino acids, including their oxidized forms which may be methionine sulfoxide or methionine sulfone, or substituted or unsubstituted It may be an aliphatic, aromatic or heteroaromatic group such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or a branched or unbranched saturated chain having 2 to 8 carbon atoms, and the aliphatic substituent is an aromatic ring or aromatic ring. It may be substituted with group heterocycle; R ⁵ is an alkyl group containing a straight or branched chain hydrocarbon having 1 to 6 carbon atoms, aromatic May be substituted on the ring or aromatic heterocyclic ring; R ⁶ is a substituted or unsubstituted aliphatic, aromatic or heteroaromatic group, for example, be a branched or unbranched saturated chain of carbon atoms 1-8 , The aliphatic substituent may be substituted with an aromatic ring or an aromatic heterocycle), and a prodrug of a pharmaceutically acceptable salt or disulfide thereof. 3. Formula III: (In the formula, R ¹ is hydrogen, an alkyl group, an aralkyl group, an acyl group, an aracyl group, an aroyl group, an alkylsulfonyl group, an aralkylsulfonyl group or an arylsulfonyl group, and the alkyl group and the acyl group each have 1 to 6 carbon atoms. R ² and R ³ are side chains of naturally occurring amino acids, or are substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups such as allyl, cyclohexyl, It may be phenyl, pyridyl, imidazolyl or a branched or unbranched saturated chain having 2 to 8 carbon atoms, the aliphatic substituent may be substituted with an aromatic ring or an aromatic heterocycle; R ⁵ is a carbon atom. An alkyl group containing a straight or branched chain hydrocarbon of formulas 1 to 6, which may be substituted with an aromatic ring or an aromatic heterocycle; n is 0, 1 or 2) , Farnesyl - compounds and pharmaceutically acceptable salts thereof to inhibit protein transferase. 4. Formula IV: (In the formula, R ¹ is hydrogen, an alkyl group, an aralkyl group, an acyl group, an aracyl group, an aroyl group, an alkylsulfonyl group, an aralkylsulfonyl group or an arylsulfonyl group, and the alkyl group and the acyl group each have 1 to 6 carbon atoms. R ² and R ³ are side chains of naturally occurring amino acids, including their oxidized forms which can be methionine sulfoxide or methionine sulfone, or substituted or unsubstituted aliphatic, It may be an aromatic or heteroaromatic group such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or a branched or unbranched saturated chain having 2 to 8 carbon atoms, and the aliphatic substituent is an aromatic ring or an aromatic heterocycle. R ⁵ is an alkyl group containing a straight or branched chain hydrocarbon having 1 to 6 carbon atoms, which is an aromatic ring or Is optionally substituted with an aromatic heterocycle), and a pharmaceutically acceptable salt or disulfide prodrug thereof. 5. N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 (S) -methylpentyl] -N-methylisoleucylhomoserine, N- [2 (S)-(2 (R) -Amino-3-mercaptopropylamino) -3 (S) -methylpentyl] -N-methylphenylalanyl homoserine, N- [2 (S)-(2 (R) -amino-3-mercaptopropyl] Amino) -3-methylbutyl] -N-methylphenylalanyl homoserine, 2 (S)-{N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 (S)-. Methylpentyl] -N-methylisoleucylamino} -2-methyl-5-hydroxypentanoic acid, 2 (S)-{N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino ) -3 (S) -me Rupentyl] -N-methylisoleucylamino} -5-methyl-5-hydroxyhexanoic acid, N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 (S)- Methylpentyl] -N-methylnorvalylhomoserine, N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 (S) -methylpentyl] -N-methylisoleucylmethionine , N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 (S) -methylpentyl] -N-methylphenylalanylmethionine, N- [2 (S)-( 2 (R) -amino-3-mercaptopropylamino) -3 (S) -methylpentyl] -N-methylnorvalylmethionine, N- [2 (S)-(2 (R) -amino-3-mercaptoprone Arylamino) -3 (S) - methylpentyl] is -N- methyl -D- nor valyl homoserine, farnesyl - compounds and pharmaceutically acceptable salts thereof to inhibit protein transferase. 6. N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 (S) -methylpentyl] -N-methylisoleucylhomoserine lactone, N- [2 (S)-( 2 (R) -amino-3-mercaptopropylamino) -3 (S) -methylpentyl] -N-methylphenylalanyl homoserine lactone, N- [2 (S)-(2 (R) -amino-3- Mercaptopropylamino) -3-methylbutyl] -N-methylphenylalanyl homoserine lactone, 3 (S)-{N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 ( S) -Methylpentyl] -N-methylisoleucylamino} -3-methyltetrahydropyran-2-one, N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) 3 (S) -methylpentyl] -N-methylnorvalylhomoserine lactone, N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 (S) -methylpentyl] -N -Methyl isoleucyl methionine methyl ester, N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 (S) -methylpentyl] -N-methylphenylalanylmethionine methyl ester , 3 (S)-{N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 (S) -methylpentyl] -N-methylisoleucylamino} -6. 6-dimethyltetrahydropyran-2-one, N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 (S) -methylpentyl] -N-methylnorvali Lumethionine methyl ester, N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 (S) -methylpentyl] -N-methyl-D-norvalylhomoserine lactone, Compounds that inhibit farnesyl-protein transferase and pharmaceutically acceptable prodrugs of its salts and disulfides. 7. N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 (S) -methylpentyl] -N-methylisoleucylhomoserine The compound according to claim 3, which is 8. N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 (S) -methylpentyl] -N-methylisoleucylhomoserine lactone The compound according to claim 4, which is 9. N- [2 (S)-(2 (R) -amino-3-mercaptopropylamino) -3 (S) -methylpentyl] -N-methylisoleucylmethionine The compound of claim 1, which is 10. N- [2 (S)-(2 (R) -amino-3-mercaptopugopyramino) -3 (S) -methylpentyl] -N-methylisoleucylmethionine methyl ester The compound according to claim 2, which is 11. A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of the compound of claim 2 dispersed therein. 12. A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of the compound of claim 4 dispersed therein. 13. A method for inhibiting farnesylation of Ras protein, which comprises administering to a non-human mammal in need of inhibition of farnesylation of Ras protein a therapeutically effective amount of the composition of claim 11. 14. A method for inhibiting farnesylation of Ras protein, which comprises administering to a non-human mammal in need of inhibition of farnesylation of Ras protein a therapeutically effective amount of the composition of claim 12. 15. A method of treating cancer, which comprises administering to the non-human mammal in need of treatment of the cancer a therapeutically effective amount of the composition of claim 11. 16. A method of treating cancer, wherein a therapeutically effective amount of the composition of claim 12 is administered to a non-human mammal in need of treatment of cancer.